1. Field of the Invention
The invention is generally directed to large dosage formulations of ribavirin.
2. Background of the Invention
Ribavirin (1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carbamide) is a broad-spectrum antiviral nucleoside analog. It is available as a capsule and tablet in both the brand and generic form in 200 mg strength. The Food and Drug Administration has approved ribavirin in combination with interferon alfa-2a or interferon alfa-2b for the treatment of hepatitis-C. Over 170 million people worldwide are chronically infected with the hepatitis-C virus (HCV). Ribavirin is available as a 200 mg tablet by Roche Laboratories under the brand COPEGUS™ and as a 200 mg capsule by Schering-Plough under the brand REBETOL™.
The most common doses prescribed for patients are 800 mg, 1000 mg, and 1200 mg per day in divided doses for both the capsule and tablet dosage forms. These dosing regimens have the patient taking up to 6 capsules or tablets per day. Ribavirin is not often given by itself; it is generally a component of a multi-drug regimen (“drug cocktail”). Therefore patients taking ribavirin have to take a large number of drugs, not in the least of which is 4 to 6 capsules or tablets of ribavirin. Not surprisingly, lack of patient compliance is a significant issue.
HCV has about a 50 percent cure rate depending upon a patient's genotype. Everything must be done to ensure patient compliance to the therapy that lasts 6 to 12 months. If dosing is more convenient for the patient, then it follows that the patient will more likely comply with the dosing regimen for the duration of therapy, which has been proven to improve patient outcomes.
Therefore, there exists a long-felt need to make the dosing of ribavirin more convenient for the patient and increase patient compliance.
From a convenience standpoint, one logical approach to the formulator would be to formulate a modified or sustained release form of ribavirin, which would result in fewer capsules or tablets taken daily. However, in the case of ribavirin, such an approach would not be successful. The pharmacokinetics of ribavirin are controlled by the rate of elimination, not absorption. Therefore, modifying the rate of release or absorption of ribavirin would not likely affect the efficacy of ribavirin. In other words, sustained release formulations of ribavirin are likely not a solution in this instance.
The present inventors have concluded that in the case of ribavirin, the optimal dosage regimen is two times a day. The inventors then strove to formulate dosage forms with a twice-a-day dosing regimen which would increase patient compliance while maintaining bioactivity similar to lower (e.g., 200 mg) dose formulations.